Dietary magnesium supplementation in cats with chronic kidney disease: A prospective double-blind randomized controlled trial.

BACKGROUND: Plasma total magnesium concentration (tMg) is a prognostic indicator in cats with chronic kidney disease (CKD), shorter survival time being associated with hypomagnesemia. Whether this risk factor is modifiable with dietary magnesium supplementation remains unexplored. OBJECTIVES: Evaluate effects of a magnesium-enriched phosphate-restricted diet (PRD) on CKD-mineral bone disorder (CKD-MBD) variables. ANIMALS: Sixty euthyroid client-owned cats with azotemic CKD, with 27 and 33 allocated to magnesium-enriched PRD or control PRD, respectively. METHODS: Prospective double-blind, parallel-group randomized trial. Cats with CKD, stabilized on a PRD, without hypermagnesemia (tMg >2.43 mg/dL) or hypercalcemia (plasma ionized calcium concentration, (iCa) >6 mg/dL), were recruited. Both intention-to-treat and per-protocol (eating ≥50% of study diet) analyses were performed; effects of dietary magnesium supplementation on clinicopathological variables were evaluated using linear mixed effects models. RESULTS: In the per-protocol analysis, tMg increased in cats consuming a magnesium-enriched PRD (ß, 0.25 ± .07 mg/dL/month; P < .001). Five magnesium supplemented cats had tMg >2.92 mg/dL, but none experienced adverse effects. Rate of change in iCa differed between groups (P = .01), with decreasing and increasing trends observed in cats fed magnesium-enriched PRD and control PRD, respectively. Four control cats developed ionized hypercalcemia versus none in the magnesium supplemented group. Log-transformed plasma fibroblast growth factor-23 concentration (FGF23) increased significantly in controls (ß, 0.14 ± .05 pg/mL/month; P = .01), but remained stable in the magnesium supplemented group (ß, 0.05±.06 pg/mL/month; P =.37). CONCLUSIONS AND CLINICAL IMPORTANCE: Magnesium-enriched PRD is a novel therapeutic strategy for managing feline CKD-MBD in cats, further stabilizing plasma FGF23 and preventing hypercalcemia.

Associations of Intact and C-Terminal FGF23 with Inflammatory Markers in Older Patients Affected by Advanced Chronic Kidney Disease.

Background: In patients with chronic kidney disease (CKD), Fibroblast Growth Factor 23 (FGF23) is markedly increased and has been proposed to interact with systemic inflammation. Methods: In this cross-sectional study, we evaluated the correlations of intact FGF23, c-terminal FGF23, and the FGF23 ratio (c-terminal to intact) with some inflammatory cytokines in 111 elderly patients with advanced CKD not yet in dialysis. Results: Estimated glomerular filtration rate (eGFR) was inversely correlated with intact FGF23 and c-terminal FGF23, as well as with interleukin 6 (IL-6), tumor necrosis factor alpha (TNFα), and monocyte chemoattractant protein-1 (MCP-1). Intact FGF23 levels were directly correlated with IL-6 (r = 0.403; p < 0.001) and TNFα (r = 0.401; p < 0.001) while c-terminal FGF23 was directly correlated with MCP-1 (r = 0.264; p = 0.005). The FGF23 ratio was, instead, inversely correlated with IL-6 (r = -0.326; p < 0.001). Multivariate analysis revealed that intact FGF23 was directly associated with TNFα [B = 0.012 (95% CI 0.006, 0.019); p = 0.003] and c-terminal FGF23 was directly associated with MCP-1 [B = 0.001 (95% CI 0.000, 0.002); p = 0.038], while the FGF23 ratio was inversely correlated with IL-6 [B = -0.028 (95% CI -0.047, -0.010); p = 0.002]. Conclusions: Our data demonstrate that, in CKD patients, intact FGF23 and the metabolites deriving from its proteolytic cleavage are differently associated with some inflammatory pathways. In particular, intact FGF23 is mainly associated with IL-6 and TNFα, c-terminal FGF23 with MCP-1, and the FGF23 ratio with IL6.

Autosomal Recessive Hypophosphatemic Rickets Type 2 Associated with a Novel ENPP1 Variant in a Taiwanese Girl.

Autosomal recessive hypophosphatemic rickets (HR) type 2 (ARHR2) is a rare form of HR caused by variant of the gene encoding ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). Our patient presented with a history of unsteady gait and progressively bowing legs that had commenced at the age of 1 year. Laboratory tests revealed an elevated level of fibroblast growth factor 23 (FGF23), hypophosphatemia, and a high urine phosphate level. Radiography revealed the typical features of rickets. Next-generation sequencing identified a previously reported c.783C>G (p.Tyr261Ter) and a novel c.1092-42A>G variant in the ENPP1 gene. The patient was prescribed oral phosphates and active vitamin D and underwent guided growth of both distal femora and proximal tibiae commencing at the age of 3 years. No evidence of generalized arterial calcification was apparent during follow-up, and growth rate was satisfactory.

Molecular Interaction of Soluble Klotho with FGF23 in the Pathobiology of Aortic Valve Lesions Induced by Chronic Kidney Disease.

Chronic kidney disease (CKD) is linked to greater prevalence and rapid progression of calcific aortic valve disease (CAVD) characterized by valvular leaflet fibrosis and calcification. Fibroblast growth factor 23 (FGF23) level is elevated, and anti-aging protein Klotho is reduced in CKD patients. However, the roles of FGF23 and Klotho in the mechanism of aortic valve fibrosis and calcification remain unclear. We hypothesized that FGF23 mediates CKD-induced CAVD by enhancing aortic valve interstitial cell (AVIC) fibrosis and calcification, while soluble Klotho inhibits FGF23 effect. Methods and Results: In an old mouse model of CKD, kidney damages were accompanied by aortic valve thickening and calcification. FGF23 levels in plasma and aortic valve were increased, while Klotho levels were decreased. Recombinant FGF23 elevated the inflammatory, fibrogenic, and osteogenic activities in AVICs. Neutralizing antibody or shRNA targeting FGF23 suppressed the pathobiological activities in AVICs from valves affected by CAVD. FGF23 exerts its effects on AVICs via FGF receptor (FGFR)/Yes-associated protein (YAP) signaling, and inhibition of FGFR/YAP reduced FGF23's potency in AVICs. Recombinant Klotho downregulated the pathobiological activities in AVICs exposed to FGF23. Incubation of FGF23 with Klotho formed complexes and decreased FGF23's potency. Further, treatment of CKD mice with recombinant Klotho attenuated aortic valve lesions. Conclusion: This study demonstrates that CKD induces FGF23 accumulation, Klotho insufficiency and aortic valve lesions in old mice. FGF23 upregulates the inflammatory, fibrogenic and osteogenic activities in AVICs via the FGFR/YAP signaling pathway. Soluble Klotho suppresses FGF23 effect through molecular interaction and is capable of mitigating CKD-induced CAVD.

Impact of Elevated Fibroblast Growth Factor 23 (FGF23) on the Cardiovascular System: A Comprehensive Systematic Literature Review.

Fibroblast growth factors (FGF) are a type of cell signaling proteins that are mostly produced by macrophages. They are essential for a variety of biological activities involved in normal development. Fibroblast growth factor 23 (FGF23) is the newest and youngest member of the FGF endocrine subfamily, along with fibroblast growth factor 19 (FGF19) and fibroblast growth factor 21 (FGF21). In this study, we conduct a systematic review of all known literature to identify the risk of elevated FGF23 in the cardiovascular system. The analysis includes the risk of cardiovascular disease for both primary and secondary causes of elevated FGF23, such as chronic renal insufficiency. This systematic literature review adhered to the Preferred Reporting Items and Meta-Analysis (PRISMA) standards. A total of 4,793 records were identified across different databases. After that, 273 records were retrieved and reviewed. After carefully examining the titles and summaries of each report, 249 additional entries were eliminated. About 24 studies from the remaining records were chosen by primary and secondary authors for screening, and they performed a quality assessment using common quality check tools. Finally, this review included 11 studies. Following a thorough analysis, we came to the conclusion that FGF23 can be regarded as a novel biomarker and should be included in the group of heart biomarkers that have already been identified, such as B-type natriuretic peptide (BNP), for the early identification of a variety of highly prevalent cardiovascular disorders.

FGF-23, Left Ventricular Hypertrophy, and Mortality in Patients With CKD: A Revisit With Mediation Analysis.

Background: In patients with chronic kidney disease (CKD), fibroblast growth factor (FGF)-23 is suspected to cause death or cardiovascular disease by inducing left ventricular hypertrophy (LVH). Objectives: This study aims to quantify the mediational effect of LVH in the hypothetical causal pathway from FGF-23 to long-term adverse outcomes. Methods: From 3,939 adults with CKD stages 2 to 4 enrolled in the CRIC (Chronic Renal Insufficiency Cohort) study, 2,368 participants with available data of FGF-23, left ventricular mass index at 1 year, and covariates were included. We employed linear and Cox proportional hazards regression models to investigate the association between FGF-23 and LVH, all-cause mortality, atrial fibrillation (AF), or congestive heart failure (CHF). Mediation analysis was used within a counterfactual framework to decompose the effect of FGF-23 into natural direct and indirect effects. Results: Among 2,368 participants (mean age: 57.7 years, 1,252 males, median FGF-23 level: 138.8 RU/mL), left ventricular mass index was positively correlated with FGF-23. During a median of 12.0, 11.1, and 11.1 years, FGF-23 was associated with all-cause mortality (HR: 1.62, 95% CI: 1.24-2.12), AF (HR: 1.58, 95% CI: 1.12-2.24), and CHF (HR: 1.32, 95% CI: 0.95-1.84) when the highest quartile was compared to the lowest quartile. LVH mediated 7.4%, 11.2%, and 21.9% of the effect of FGF-23 on all-cause mortality, AF, and CHF, respectively. Conclusions: In CKD patients, FGF-23 had a minor effect on the development of long-term adverse outcomes through LVH. Other potential mediators and the validity of negative effect of FGF-23 should be explored.

The relationship between phosphorus retention and fibroblast growth factor 23 in broiler breeders.

Previous studies with broiler breeders indicate a P retention threshold when fed daily dietary levels of non-phytate P (NPP) exceeding 320 mg. Fibroblast growth factor 23 (FGF23) is a hormone secreted by osteocytes which modulates P retention and could be the biological agent which controls the P threshold in breeders. To evaluate the relationship between FGF23 and the P retention threshold, a 4-wk study with 32-wk-old breeders was conducted with 6 dietary treatments with daily NPP intake of 216 to 576 mg/d/h with increments of 80 mg/kg diet. The goals were 1) to elucidate how plasma FGF23 corresponds with the P retention threshold in broiler breeders and 2) to determine the amount of P for optimal egg production and bone health. Results showed that between daily 288 mg and 360 mg dietary NPP intake, P retention decreased from 33 to 26% but FGF23 levels increased from 130 pg/mL to 220 pg/mL with increasing NPP. The elevation of plasma FGF23 between the range of 288 mg to 360 mg dietary NPP/d intake suggests that FGF23 is related to the P retention threshold and may be the major hormone for regulating physiological P levels when intake of daily dietary P levels are increased above 288 mg NPP.

X-Linked hypophosphatemia. Data from a Spanish adult population cohort.

BACKGROUND: X-linked hypophosphatemia (XLH) represents the most prevalent cause of hereditary hypophosphatemia. X-linked hypophosphatemia causes an elevation of fibroblast growth factor 23 (FGF23), a hormone responsible for inducing hyperphosphaturia, and reduced active vitamin D synthesis. Challenges in diagnosis and the absence of well-defined clinical guidelines have resulted in higher rates of late diagnoses. While numerous reports focus on pediatric X-linked hypophosphatemia patients, studies in adults are limited. METHODS: Multicenter, cross-sectional, observational study of a cohort of adult patients diagnosed with X-linked hypophosphatemia. The study identified demographic, clinical, genetic, laboratory variables, treatments used, comorbidities, and complications. RESULTS: Twenty patients diagnosed with X-linked hypophosphatemia were collected. The median age at diagnosis was 11 (1-56) years and at data collection was 44 (21-68) years. Fifty percent of cases were diagnosed in adulthood. Main clinical manifestation was osteoarticular pain, in 75% of cases, and no relation to age at diagnosis, height, phosphorus, or parathyroid hormone (PTH) levels was observed (p > 0.05). Lower limb deformities were associated with reduced stature and earlier diagnosis (p < 0.05). Sixty percent of patients reported pain requiring chronic medication and no significant correlation was found with other variables. Anxiety and depression were found in an important number of patients. FGF23 levels were not related to any of the clinical variables studied (p > 0.05). DISCUSSION: This is the largest study on adult patients with X-linked hypophosphatemia in southern Europe. It may offer valuable insights into the natural progression and course of the condition in adults, which can aid in better clinical management.

Skeletal Muscle Injury in Chronic Kidney Disease-From Histologic Changes to Molecular Mechanisms and to Novel Therapies.

Chronic kidney disease (CKD) is associated with significant reductions in lean body mass and in the mass of various tissues, including skeletal muscle, which causes fatigue and contributes to high mortality rates. In CKD, the cellular protein turnover is imbalanced, with protein degradation outweighing protein synthesis, leading to a loss of protein and cell mass, which impairs tissue function. As CKD itself, skeletal muscle wasting, or sarcopenia, can have various origins and causes, and both CKD and sarcopenia share common risk factors, such as diabetes, obesity, and age. While these pathologies together with reduced physical performance and malnutrition contribute to muscle loss, they cannot explain all features of CKD-associated sarcopenia. Metabolic acidosis, systemic inflammation, insulin resistance and the accumulation of uremic toxins have been identified as additional factors that occur in CKD and that can contribute to sarcopenia. Here, we discuss the elevation of systemic phosphate levels, also called hyperphosphatemia, and the imbalance in the endocrine regulators of phosphate metabolism as another CKD-associated pathology that can directly and indirectly harm skeletal muscle tissue. To identify causes, affected cell types, and the mechanisms of sarcopenia and thereby novel targets for therapeutic interventions, it is important to first characterize the precise pathologic changes on molecular, cellular, and histologic levels, and to do so in CKD patients as well as in animal models of CKD, which we describe here in detail. We also discuss the currently known pathomechanisms and therapeutic approaches of CKD-associated sarcopenia, as well as the effects of hyperphosphatemia and the novel drug targets it could provide to protect skeletal muscle in CKD.

Circulating Levels of Soluble α-Klotho and FGF23 in Childhood Cancer Survivors: Lack of Association with Nephro- and Cardiotoxicity-A Preliminary Study.

Background/Objectives: The survival rate among pediatric cancer patients has reached 80%; however, these childhood cancer survivors (CCSs) are at a heightened risk of developing chronic conditions in adulthood, particularly kidney and cardiovascular diseases. The aims of this study were to assess the serum α-Klotho and FGF23 levels in CCSs and to determine their association with nephro- and cardiotoxicity. Methods: This study evaluated a cohort of 66 CCSs who remained in continuous remission, with a mean follow-up of 8.41 ± 3.76 years. Results: The results of this study revealed that CCSs exhibited significantly higher levels of soluble α-Klotho compared to healthy peers (1331.4 ± 735.5 pg/mL vs. 566.43 ± 157.7 pg/mL, p < 0.0001), while no significant difference was observed in their FGF23 levels. Within the participant cohort, eight individuals (12%) demonstrated a reduced estimated glomerular filtration rate (eGFR) below 90 mL/min/1.73 m2. The relationship between treatment with abdominal radiotherapy and reduced eGFR was confirmed (p < 0.05). No correlations were found between potential treatment-related risk factors, such as chemotherapy or radiation therapy, serum levels of α-Klotho and FGF23, and nephro- and cardiotoxicity. Conclusions: In conclusion, this preliminary cross-sectional study revealed elevated levels of α-Klotho among childhood cancer survivors but did not establish a direct association with anticancer treatment. The significance of elevated α-Klotho protein levels among CCSs warrants further investigation.

Relationship between fibroblast growth factor in plasma and carotid plaque neovascularization: a pilot study.

Background: Unstable atherosclerotic carotid plaques with intraplaque neovascularization (IPN) carry a substantial risk for ischemic stroke. Conventional ultrasound methods fall short in detecting IPN, where superb microvascular imaging (SMI) has emerged as a promising tool for both visualizing and quantification. High levels of fibroblast growth factor 23 (FGF-23) have, in observational studies, been suggested as related to cardiovascular morbidity and mortality. The association of FGF-23 to atherosclerotic carotid plaque instability remains relatively unexplored. Methods: A cohort of twenty-nine patients with ≥50% atherosclerotic carotid stenosis underwent conventional carotid ultrasound, SMI, and blood tests, including measurement of FGF-23 in plasma. Nineteen patients were characterized as symptomatic and ten as asymptomatic. Results: Our major findings were: i) Higher FGF-23 levels were strongly correlated with increased SMI-assessed IPN. ii) Neo-vessel count recorded by quantitative SMI was positively correlated to increased FGF-23 levels, but not with basic FGF levels. (iii) In contrast, traditional risk factors for plaque instability exhibited no noteworthy associations with SMI-assessed IPN or with FGF-23 levels. Conclusion: This pilot study suggest the potential of FGF-23 as a valuable marker for neovascularization and atherosclerotic carotid plaque instability as a risk factor for ischemic stroke. Further research involving larger cohorts and prospective data is necessary to understand FGF-23's role in this context comprehensively.

The Intricacies of Renal Phosphate Reabsorption-An Overview.

To maintain an optimal body content of phosphorus throughout postnatal life, variable phosphate absorption from food must be finely matched with urinary excretion. This amazing feat is accomplished through synchronised phosphate transport by myriads of ciliated cells lining the renal proximal tubules. These respond in real time to changes in phosphate and composition of the renal filtrate and to hormonal instructions. How they do this has stimulated decades of research. New analytical techniques, coupled with incredible advances in computer technology, have opened new avenues for investigation at a sub-cellular level. There has been a surge of research into different aspects of the process. These have verified long-held beliefs and are also dramatically extending our vision of the intense, integrated, intracellular activity which mediates phosphate absorption. Already, some have indicated new approaches for pharmacological intervention to regulate phosphate in common conditions, including chronic renal failure and osteoporosis, as well as rare inherited biochemical disorders. It is a rapidly evolving field. The aim here is to provide an overview of our current knowledge, to show where it is leading, and where there are uncertainties. Hopefully, this will raise questions and stimulate new ideas for further research.

A role for sirtuin 1 in FGF23 activation following ß-glycerophosphate treatment.

Phosphate homeostasis is vital for many biological processes and disruptions in circulating levels can be detrimental. While the mechanisms behind FGF23 regulation have been regularly studied, the role of extracellular phosphate sensing and its impact on fibroblast growth factor 23 (FGF23) expression remains unclear. This study aimed to investigate the involvement of reactive oxygen species (ROS), silent information regulator 1 (SIRT1), and Hairy and Enhancer of Split-1 (HES1) in regulating FGF23 in FGF23 expressing MC3T3-E1 cells. MC3T3-E1 cells treated with ß-glycerophosphate (BGP) resulted in increased Fgf23 expression. Inhibition of ROS formation by inhibition of NADPH oxidase, which is essential for ROS production, did not affect this response to BGP, suggesting ROS is not involved in this process. Moreover, treatment with tert-butyl hydroperoxide (TBHP), a ROS-inducing agent, did not increase Fgf23 expression. This suggests that ROS machinery is not involved in FGF23 stimulation as previously suggested. Nonetheless, inhibition of SIRT1 using Ex527 eliminated the Fgf23 response to BGP, indicating its involvement in FGF23 regulation after BGP treatment. Indeed, activation of SIRT1 using SRT1720 increased Fgf23 expression. Moreover, transcription factor Hes1 was upregulated by BGP treatment, which was diminished when cells were treated with Ex527 implying it is also regulated through SIRT1. These findings suggest the existence of an upstream SIRT1-HES1 axis in the regulation of FGF23 by phosphate, though we were unable to find a role for ROS in this process. Further research should provide insights into phosphate homeostasis and potential therapeutic targets for phosphate-related disorders.

Tumor-Induced Osteomalacia due to Sarcomatoid Non-Small Cell Lung Carcinoma Confounded by Drug-Induced Fanconi Syndrome.

Tumor-induced osteomalacia (TIO) is an exceedingly rare paraneoplastic condition characterized by hypophosphatemia, osteomalacia, fragility fractures, and fatigue. A 39-year-old man was assessed for hemoptysis, pathological rib fractures, and fatigue, and was found to have a chest mass with lung metastasis. Biopsy of the mass suggested high-grade epithelioid and spindle cell neoplasm. He was initially treated for soft tissue sarcoma with an ifosfamide-based regimen and developed Fanconi syndrome that resolved on cessation of ifosfamide. Serum phosphate remained low. A low tubular maximum reabsorption of phosphate to glomerular filtration rate ratio (TmP/GFR) indicated disproportionate phosphaturia, while a severely elevated fibroblast growth factor-23 (FGF23) level enabled a diagnosis of TIO. He was started on phosphate and calcitriol supplementation. Subsequent next-generation sequencing demonstrated a RET-fusion mutation, leading to reclassification of his malignancy to a sarcomatoid non-small cell lung carcinoma. He was switched to selpercatinib, a targeted RET-kinase inhibitor approved for locally advanced or metastatic RET-fusion-positive solid tumors. This induced tumor remission with subsequent normalization of his FGF23 levels and hypophosphatemia. Despite the presence of a confounding etiology like drug-induced Fanconi syndrome, persistence of hypophosphatemia should prompt a workup of TIO, especially in the presence of a tumor.

FGF23 as a Potential Pathophysiological Factor in Peripheral Arterial Disease Associated with Chronic Kidney Disease.

Fibroblast growth factor 23 (FGF23) levels are often elevated in chronic kidney disease (CKD). FGF23 and inflammation are common characteristics in CKD, and both are associated with worse disease progression and the occurrence of complications. The existence of an interaction between FGF23 and inflammation has been suggested, each of which influences the expression and activity of the other, leading to a vicious feedback loop with adverse outcomes, including cardiovascular disease and mortality. In this work, we determined circulating FGF23 levels in a group of patients with CKD stages 3 and 4 subjected to elective femoral endarterectomy due to established peripheral artery disease (PAD), a condition resulting from an athero-inflammatory process, and we studied its associations with different inflammatory markers and mediators. We evaluated its association with serum tumor necrosis factor (TNF)α, interleukin (IL) 6, and IL10, as well as with the gene expression levels of these parameters and A disintegrin and metalloproteinase domain-containing protein (ADAM) 17 in femoral vascular tissue and peripheral blood circulating cells (PBCCs). We also analyzed its association with serum concentrations of C-reactive protein (CRP), the systemic immune inflammation index (SII), and the neutrophil-to-lymphocyte ratio (NLR). Finally, we determined the vascular immunoreactivity of protein TNFα in a subgroup of patients. FGF23 concentrations were independently associated with circulating and PBCC mRNA levels of TNFα. Worst kidney function and diabetes were also found to be contributing to FGF23 levels. Patients with higher levels of FGF23 also had greater vascular immunoreactivity for TNFα.

A novel miR-466l-3p/FGF23 axis promotes osteogenic differentiation of human bone marrow mesenchymal stem cells.

BACKGROUND: MicroRNAs (miRNAs) regulate osteogenic differentiation processes and influence the development of osteoporosis (OP). This study aimed to investigate the potential role of miR-466 l-3p in OP. METHODS: The expression levels of miR-466 l-3p and fibroblast growth factor 23 (FGF23) were quantified in the trabeculae of the femoral neck of 40 individuals with or without OP using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The impact of miR-466 l-3p or FGF23 expression on cell proliferation and the expression levels of runt-related transcription factor 2 (RUNX2), type I collagen (Col1), osteocalcin (OCN), osterix (OSX) and dentin matrix protein 1 (DMP1) was quantified in human bone marrow mesenchymal stem cells (hBMSCs) overexpressing miR-466 l-3p. Furthermore, alkaline phosphatase (ALP) staining and alizarin red staining were performed to measure ALP activity and the levels of calcium deposition, respectively. In addition, bioinformatics analysis, luciferase reporter assays, and RNA pull-down assays were conducted to explore the molecular mechanisms underlying the effects of miR-466 l-3p and FGF23 in osteogenic differentiation of hBMSCs. RESULTS: The expression levels of miR-466 l-3p were significantly lower in femoral neck trabeculae of patients with OP than in the control cohort, whereas FGF23 levels exhibited the opposite trend. Furthermore, miR-466 l-3p levels were upregulated and FGF23 levels were downregulated in hBMSCs during osteogenic differentiation. Moreover, the high miR-466 l-3p expression enhanced the mRNA expression of RUNX2, Col1, OCN, OSX and DMP1, as well as cell proliferation, ALP activity, and calcium deposition in hBMSCs. FGF23 was found to be a direct target of miR-466 l-3p. FGF23 overexpression downregulated the expression of osteoblast markers and inhibited the osteogenic differentiation induced by miR-466 l-3p overexpression. qRT-PCR and Western blot assays showed that miR-466 l-3p overexpression decreased the expression levels of mRNAs and proteins associated with the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, whereas FGF23 upregulation exhibited the opposite trend. CONCLUSION: In conclusion, these findings suggest that miR-466 l-3p enhances the osteogenic differentiation of hBMSCs by suppressing FGF23 expression, ultimately preventing OP.

S100a8/9 (S100 Calcium Binding Protein a8/9) Promotes Cardiac Hypertrophy Via Upregulation of FGF23 (Fibroblast Growth Factor 23) in Mice.

BACKGROUND: S100a8/9 (S100 calcium binding protein a8/9) belongs to the S100 family and has gained a lot of interest as a critical regulator of inflammatory response. Our previous study found that S100a8/9 homolog promoted aortic valve sclerosis in mice with chronic kidney disease. However, the role of S100a8/9 in pressure overload-induced cardiac hypertrophy remains unclear. The present study was to explore the role of S100a8/9 in cardiac hypertrophy. METHODS AND RESULTS: Cardiomyocyte-specific S100a9 loss or gain of function was achieved using an adeno-associated virus system, and the model of cardiac hypertrophy was established by aortic banding-induced pressure overload. The results indicate that S100a8/9 expression was increased in response to pressure overload. S100a9 deficiency alleviated pressure overload-induced hypertrophic response, whereas S100a9 overexpression accelerated cardiac hypertrophy. S100a9-overexpressed mice showed increased FGF23 (fibroblast growth factor 23) expression in the hearts after exposure to pressure overload, which activated calcineurin/NFAT (nuclear factor of activated T cells) signaling in cardiac myocytes and thus promoted hypertrophic response. A specific antibody that blocks FGFR4 (FGF receptor 4) largely abolished the prohypertrophic response of S100a9 in mice. CONCLUSIONS: In conclusion, S100a8/9 promoted the development of cardiac hypertrophy in mice. Targeting S100a8/9 may be a promising therapeutic approach to treat cardiac hypertrophy.

Roles of Parathyroid Hormone and Fibroblast Growth Factor 23 in Advanced Chronic Kidney Disease.

Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) each play a central role in the pathogenesis of chronic kidney disease (CKD)-mineral and bone disorder. Levels of both hormones increase progressively in advanced CKD and can lead to damage in multiple organs. Secondary hyperparathyroidism (SHPT), characterized by parathyroid hyperplasia with increased PTH secretion, is associated with fractures and mortality. Emerging evidence suggests that these associations may be partially explained by PTH-induced browning of adipose tissue and increased energy expenditure. Observational studies suggest a survival benefit of PTHlowering therapy, and a recent study comparing parathyroidectomy and calcimimetics further suggests the importance of intensive PTH control. The mechanisms underlying the regulation of FGF23 secretion by osteocytes in response to phosphate load have been unclear, but recent experimental studies have identified glycerol-3-phosphate, a byproduct of glycolysis released by the kidney, as a key regulator of FGF23 production. Elevated FGF23 levels have been shown to be associated with mortality, and experimental data suggest off-target adverse effects of FGF23. However, the causal role of FGF23 in adverse outcomes in CKD patients remains to be established. Further studies are needed to determine whether intensive SHPT control improves clinical outcomes and whether treatment targeting FGF23 can improve patient outcomes.

Alterations in regulators of the renal-bone axis, inflammation and iron status in older people with early renal impairment and the effect of vitamin D supplementation.

CONTEXT: Chronic kidney disease (CKD) leads to alterations in fibroblast growth factor 23 (FGF23) and the renal-bone axis. This may be partly driven by altered inflammation and iron status. Vitamin D supplementation may reduce inflammation. OBJECTIVE AND METHODS: Older adults with early CKD (estimated glomerular filtration rate (eGFR) 30-60 ml/min/1.73 m2; CKDG3a/b; n = 35) or normal renal function (eGFR >90 ml/min/1.73 m2; CKDG1; n = 35) received 12,000, 24,000 or 48,000 IU D3/month for 1 year. Markers of the renal-bone axis, inflammation and iron status were investigated pre- and post-supplementation. Predictors of c-terminal and intact FGF23 (cFGF23; iFGF23) were identified by univariate and multivariate regression. RESULTS: Pre-supplementation, comparing CKDG3a/b to CKDG1, plasma cFGF23, iFGF23, PTH, sclerostin and TNFα were significantly higher and Klotho, 1,25-dihydroxyvitamin D and iron were lower. Post-supplementation, only cFGF23, 25(OH)D and IL6 differed between groups. The response to supplementation differed between eGFR groups. Only in the CKDG1 group, phosphate decreased, cFGF23, iFGF23 and procollagen type I N-propeptide increased. In the CKDG3a/b group, TNFα significantly decreased, and iron increased. Plasma 25(OH)D and IL10 increased, and carboxy-terminal collagen crosslinks decreased in both groups. In univariate models cFGF23 and iFGF23 were predicted by eGFR and regulators of calcium and phosphate metabolism at both time points; IL6 predicted cFGF23 (post-supplementation) and iFGF23 (pre-supplementation) in univariate models. Hepcidin predicted post-supplementation cFGF23 in multivariate models with eGFR. CONCLUSION: Alterations in regulators of the renal-bone axis, inflammation and iron status were found in early CKD. The response to vitamin D3 supplementation differed between eGFR groups. Plasma IL6 predicted both cFGF23 and iFGF23 and hepcidin predicted cFGF23.